Department of Dermatology, University of Pennsylvania Medical School, Philadelphia, PA, USA.
Exp Dermatol. 2010 Jun;19(6):493-500. doi: 10.1111/j.1600-0625.2010.01081.x. Epub 2010 Apr 20.
Curcuminoids exhibit anti-proliferative properties in many cell lines by modulating signalling pathways to inhibit cell growth. However, the specific effects of curcuminoids on human keratinocytes are not well defined, and this situation impairs mechanistic thinking regarding potential therapeutic uses. We hypothesized that curcuminoids would modulate key growth regulatory pathways in keratinocytes to inhibit cell proliferation. To test this hypothesis, the effects of curcumin and tetrahydrocurcumin (THC) on mitogen-activated protein (MAP) kinase signalling in keratinoctyes were determined. Primary human keratinocytes treated with curcumin or THC demonstrated decreased activation of p44/42 MAP kinases but increased levels of activated p38 MAP kinases. These data suggest that curcuminoids specifically activate stress-induced MAP kinases while inhibiting mitogen-induced MAP kinases. Curcuminoids also promote the phosphorylation of p53 on serine 15 in a dose-dependent and p38-dependent manner, suggesting that these compounds may activate p53. The effects of curcuminoids on keratinocytes mirrored some aspects of UVB and could be inhibited by N-acetylcysteine, suggesting that these compounds activate p38 through a mechanism that involves glutathione depletion. Both curcuminoids induced G2/M block and inhibited keratinocyte growth, and THC increased cellular levels of p21, a known p53 transcriptional target. These data demonstrate that curcuminoids can differentially regulate MAP kinases to inhibit keratinocyte growth while inducing p21. Curcuminoids also synergize with UVB to enhance p53 phosphorylation. The findings provide a rationale for testing curcuminoids in disorders associated with impaired p53 function or in which UVB-treatment is efficacious.
姜黄素类通过调节信号通路抑制细胞生长来抑制许多细胞系的增殖。然而，姜黄素类对人类角质形成细胞的具体作用尚不清楚，这种情况阻碍了对潜在治疗用途的机制思考。我们假设姜黄素类会调节角质形成细胞中的关键生长调节途径以抑制细胞增殖。为了验证这一假设，研究了姜黄素和四氢姜黄素 (THC) 对丝裂原激活蛋白 (MAP) 激酶信号在角质形成细胞中的作用。用姜黄素或 THC 处理的原代人角质形成细胞显示 p44/42 MAP 激酶的激活减少，但激活的 p38 MAP 激酶水平增加。这些数据表明姜黄素类特异性地激活应激诱导的 MAP 激酶，同时抑制有丝分裂原诱导的 MAP 激酶。姜黄素类还以剂量依赖性和 p38 依赖性方式促进 p53 丝氨酸 15 的磷酸化，表明这些化合物可能激活 p53。姜黄素类对角质形成细胞的作用反映了 UVB 的某些方面，并且可以被 N-乙酰半胱氨酸抑制，这表明这些化合物通过涉及谷胱甘肽耗竭的机制激活 p38。两种姜黄素类都诱导 G2/M 阻滞并抑制角质形成细胞生长，并且 THC 增加了 p21 的细胞水平，p21 是已知的 p53 转录靶标。这些数据表明，姜黄素类可以通过差异调节 MAP 激酶来抑制角质形成细胞生长，同时诱导 p21。姜黄素类还与 UVB 协同作用以增强 p53 磷酸化。这些发现为在与 p53 功能受损相关的疾病或其中 UVB 治疗有效的疾病中测试姜黄素类提供了依据。
